The long-term goal of this project is to understand the molecular mechanisms and signaling processes involved in the development and differentiation of chondrocytes. Hox genes, which encode transcription factors, have been shown to be crucial for proper patterning of skeletal elements during development. There is recent evidence suggesting that Hox genes are also important regulators of cartilage differentiation. In our laboratory, overexpression of Hoxc-8 in transgenic mice leads to increased proliferation of chondrocytes at the expense of differentiation. Our hypothesis for the proposed study is that Hoxc-8 is involved in regulating the rate of chondrocyte proliferation and/or differentiation. The specific aims of this project are to: 1) characterize the expression of Hoxc-8 throughout all stages of chondrogenesis; 2) determine the biological role of Hoxc-8 in chondrocyte development by studying its ability to maintain the proliferative state and/or to regulate the progression of chondrocytes to a terminally differentiated state; and 3) identify the growth and differentiation signals regulated by Hoxc-8 during chondrogenesis. The data obtained from these studies should aid in our understanding of the biology of cartilage development and regeneration. Insight into the molecular mechanism(s) involved in cartilage development will have therapeutic implications for fracture repair and human disease states, such as osteoarthritis.